Current and historical procedures for the treatment of colon and rectal cancer have been based, for staging purposes, upon the natural history of tumor spread, and thence, upon operative and non-operative options. Operative options generally have looked to the physical location and surgical resection of tumor. A variety of techniques have been brought to bear in the art with the purpose of aiding the surgeon in detecting and localizing neoplastic tissue as part of this surgical procedure. ("Neoplastic tissue", for present purposes, often is referred to as cancerous tissue, though malignant tumor and malignant tumor cells also are found in the terminology of the art. The term "neoplastic tissue" includes all of these.) A substantial amount of effort in aiding the surgeon in locating neoplastic tissue has been through the utilization of radiolabeled antibody for detection purposes For example, one technique includes the scintillation scanning of patients injected with relatively high energy, e.g. .sup.131 I labeled antibodies. Such photoscanning or scintillation scanning provides scintigrams difficult to interpret because of blood pool background radioactivity. Computer subtraction of radioactive blood pool agents and the use of two labeled antibodies (one specific for the tumor and one non-specific) have been attempted to enhance imaging. Nevertheless, such techniques have been found to provide little, if any, useful information to the surgeon, especially over and above CAT scans, magnetic resonance imagings, and like traditional techniques. Typically, large tumor is readily located by the surgeon by visualization at the operating theater and, in particular, through palpation, i.e. the feel of a tumor as opposed to that of normal tissue. To achieve operative success, however, it is necessary for the surgeon to somehow locate "occult" tumor, i.e. tumor which cannot be found by the conventional surgical procedures of sight and feel. Failure to locate and remove such occult tumor generally will result in the continued growth of cancer in the patient, a condition often referred to as "recurrent" cancer. In general, conventional diagnostic techniques as, for example, use of the classic gamma camera and the like, fail to find or locate occult tumor. As tumor sites become smaller, the radionucleide concentrations at given tumor site will tend to be lost, from an imaging standpoint, in the background where blood pool radiation necessarily is present in the patient.
U.S. Pat. No. 4,782,840 by Martin, M.D. and Thurston, Ph.D., entitled "Method for Locating, Differentiating, and Removing Neoplasms", issued Nov. 8, 1988 (the disclosure of which is expressly incorporated herein by reference) reviews such scintillation scanning techniques and discloses a much improved method for locating, differentiating, and removing neoplasms. Such technique utilizes a radiolabeled antibody and a portable radiation detection probe which the surgeon may use intraoperatively in order to detect sites of radioactivity. Because of the proximity of the detection probe to the labeled antibody, the faint radiation emanating from occult sites becomes detectable, for example, in part because of the inherent application of the approximate inverse square law of radiation propagation. The procedure is known as the RIGS system (RIGS being a trademark of Neoprobe Corporation, Columbus, Ohio) and is successful additionally because of a recognition that tumor detection should be delayed until the blood pool background of circulating radiolabeled antibody has had an opportunity to be cleared from the body. As a consequence, the photon emissions or radiation emitted by minor tumors compared to surrounding tissue becomes detectable in view of the proximity of the probe device to it. Fortuitously, the '840 patent discloses the ability of the radiolabeled antibody to remain bound to or associated with neoplastic tissue for extended periods of time with the radio tag still bound thereto. Moreover, even though the accretion of radioactivity at the tumor site decreases over time, the blood pool background and surrounding tissue (relative to the tumor sites) decrease at a much greater rate so that the radioactive sites can be determined readily utilizing a hand held probe positioned in close proximity with the tissue under investigation.
A highly important aspect of all procedures associated with colorectal and other cancers resides in the proper staging of the patient according to the extent and severity of the disease. Such staging aids in determining the appropriate post-surgical treatment for such patients. Stage I and II patients are believed to be curable by surgery alone, whereas Stage III patients, i.e. patients determined to have cancer spread to the lymph nodes, are treated with some form of post-operative therapy, such as chemotherapy. Stage IV patients, i.e. patients with metastisis to other organs, are treated with a variety of methods, including post-surgical therapy and/or surgical removal of the primary tumor. More severe metastisis typically is not deemed to be treatable by surgery and thus, surgery is not undertaken in order to spare the patients unnecessary trauma. Where the above-noted hidden or occult cancer is not found, residual disease is left behind and is not accounted for with respect to an evaluation of the extent of the disease to determine proper post-surgical therapy.
Colorectal cancer may spread by local invasion, lymphatic extension, hematogenous spread, or implantation. After the initial mucosal growth, a tumor may progress locally in several directions, but usually it protrudes first into the lumen. Mural penetration may result in local failure or peritoneal seeding.
Colorectal cancer first metastasizes to the perirectal nodes at the level of the primary tumor or immediately above it. Next, the chain accompanying the superior hemorrhoidal vessels is involved. In later stages of disease, when the hemorrhoidal lymphatics are blocked, there is lateral downward spread. In colon carcinoma, normal lymphatic flow is through the lymphatic channels along the major arteries, with three echelons of lymph nodes: pericolic, intermediate, and principal. If tumors lie between two major vascular pedicles, lymphatic flow may drain in either or both directions. If the central lymph nodes are blocked by tumor, lymphatic flow can become retrograde along the marginal arcades proximally and distally. The risk for lymph node metastases increases with increasing tumor grade, as does the number of lymph nodes affected.
The liver is the primary site of hematogenous metastases, followed by the lung. Involvement of other sites in the absence of liver or lung involvement is rare.
Implantation refers to the release of tumor cells from the primary tumor and their deposition on another surface. Implantation has been reported with tumor cells shed intraluminally, from the serosal surface through the peritoneum, and by surgical manipulation and resultant deposition on wound surfaces.
The contribution of RIGS-based surgery to enhancing the vision-based and touch-based procedures of the surgeon has been substantial. The detection and location approach of this system has permitted the identification and removal of hidden or occult tumor under conditions where otherwise conventional procedures would not have found it. Additionally, the system has been employed in staging, particularly in evaluating lymph nodes and other metastatic disease for staging procedures. The system has been demonstrated in clinical studies to substantially improve the staging of primary colorectal cancer patients which, having been staged by traditional means, were restaged to State III disease based upon the RIGS system as confirmed by pathology findings. As a consequence of such findings, patients so re-evaluated are eligible for post-surgical therapy, such as chemotherapy, resulting in improved patient management. The importance of such staging has been established in view of the National Institute of Health (NIH) consensus report concerning the administration of adjuvant chemotherapy to appropriately stage patients. "NIH Consensus Conference: Adjuvant Therapy for Patients with Colon and Rectal Cancer", JAMA, 1990; 264:1444-50.
The procedure carried out in the course of RIGS-based colorectal surgery involves, inter alia, a radionuclide survey of the lymph system and organs within the peritoneal cavity. Where a lymph node has been identified by the surgeon in the course of such survey by its association with a radiolabel in the course of surgery, it will be resected and immediately delivered to a tumor pathologist for intraoperative consultation. For this consultation, the pathologist typically carries out a somewhat standard technique which involves a sampling of the lymph node or tissue received, freezing, cutting of sections in a crystal, staining of those sections with hematoxylin-eosin or an equivalent stain, and examination under a microscope. Ideally, this procedure takes about five minutes per specimen, although extra time is allowed if multiple sections of specimens are to be examined. See in this regard, Cancer, Principles & Practice of Oncology, 4th Ed., vol. 1, p. 235, J.B. Lippincott Company, Philadelphia.
Because of the high sensitivity of the RIGS system, lymph node involvement may be identified at very early stages of colorectal cancer metastisis. This sensitivity may be occasioned by a form of biological amplification occurring wherein the radiolabeling system serves to identify sialomucin, a substance secreted by cancer involved cells, as opposed to the cells themselves. As a consequence, involved lymph nodes found positive by a radionuclide survey in the course of surgery which are delivered to the tumor pathologist may contain only a limited number of cancerous cells. Severely constrained by the time limitations of interoperative consultation, the pathologist often will not section a sample at the correct position and thus reports the resultant negative analysis to the surgeon. As is apparent, a technique is called for to aid the tumor pathologist in determining the proper location upon the specimen for carrying out sectioning with the highest probability of locating cell involvement in cancer.